GP6 rs2304166 polymorphism is associated with response to natalizumab in multiple sclerosis patients

Currently, there are few established pharmacogenetic predictors of response to treatment in multiple sclerosis (MS) patients. Commonly used second line treatments include natalizumab that has proven to be successful in slowing MS progression in a subset of patients. Our aim was to identify pharmacogenetic factor(s) associated with MS patients’ response to natalizumab. Ten MS patients not responding to natalizumab and 23 MS patients responsive to natalizumab were selected for exome sequencing. Exome sequences were analyzed and resultant variant was assessed in an additional cohort of 86 MS patients. Exome analysis revealed a missense polymorphism (rs2304166) in glycoprotein VI ( GP6 ) gene (19q13.42, c.940C > G, p.P314A) associated in homozygosity with MS poor response to natalizumab ( p = 0.0012). An additional cohort of 86 MS patients of which 19 were natalizumab unresponsive and 67 responsive confirmed rs2304166 CC significant association with poor response to natalizumab ( p = 0.0000027). In addition, rs2304166 CC MS patients had increased MS disability despite taking natalizumab (Odds ratio 22.18, 95% CI: 5.758–95.88, p = 0.00000001). Natalizumab is a commonly used second line treatment for MS, and poor response to natalizumab appears to be associated with rs2304166 CC genotype in MS patients. Our findings suggest the need to investigate GP6 ’s rs2304166 role as a potential pharmacogenetic predictor for MS patients’ response to natalizumab.